The present invention relates to a nociceptin antagonist containing a novel amide derivative or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to an analgesic containing, as an active ingredient, a novel amide derivative or a pharmaceutically acceptable salt thereof, which show analgesic effect as nociceptin antagonist by selectively acting on an opioid receptor like-1 receptor and which are useful for the treatment of pain, particularly sharp pain or pain caused by sensory nerve abnormality, such as hyperalgesia and allodynia. The present invention moreover relates to a novel use of a certain kind of amide derivative as a nociceptin antagonist and analgesic.
Pain is a sensation felt by anybody and is an important vital signal or alarm signal.
Pain caused by injury, surgery, inflammation and the like, as well as chronic pain stemming from injury, dysfunction and the like of nerves after recovery from an injury is one of the major clinical problems. Chronic pain sometimes causes autonomic disorder, dyskinesia or mental disorder, wherein the pain itself is the cause of a different disease.
There is also known to exist pain due to sensory nerve abnormality, such as hyperalgesia associated with promotion of reaction in response to an ordinary pain stimulus, allodynia wherein pain is felt in response to a stimulus that normally causes no pain, and the like.
Analgesics are divided into central analgesic and peripheral analgesic according to the main action site thereof. Inasmuch as the cause of pain is a complicated entanglement of autonomic nerve reactions, feeling and the like, sedative, antianxiety, antidepressant, hypnotic, antispasmodic, vasodilator and the like are used as analgesic auxiliary agents.
Central analgesics are roughly divided into narcotic analgesic, anarcotic analgesic and antipyretic analgesic.
Narcotic and anarcotic opioids have been used for the treatment of sharp pain such as postoperative pain and myocardial infarction, burn and the like. These analgesics show noticeable effects resulting from a strong analgesic action combined with an action to remove fear of pain. On the other hand, narcotic analgesics accompany physical dependence and mental dependence and express withdrawal syndrome by drug dependence. Other side effects of respiratory suppresion, nausea, emesis, constipation, dysuria and the like restrict their use.
Antipyretic analgesic is effective for superficial pain, such as toothache, myalgia and the like, but is considered to be ineffective for visceralgia. Its antipyretic action is considered to focus on hypothalamus thermoregulation center, and analgesic action is mainly exerted via peripheral nerves. However, there are many unknown parts in the central action mechanism thereof. Its analgesic effect is generally weaker than that offered by narcotic and anarcotic opioids. Consequently, sharp pain is cautiously treated with narcotic and anarcotic opioids in clinical situations to the extent that causes less side effects.
Although more than 20 years have passed since the analgesic effect of morphine by intrathecal administration to human was confirmed and morphine was first applied to clinical situations, a pharmaceutical agent exceeding morphine in terms of various side effects, histotoxicity to spinal cord and the like, that accompany analgesic effect of morphine, has not been found.
Certain pain caused by injury and functional disorder of nerves and the like is resistant to analgesics currently in clinical use, such as antipyretic analgesic and narcotic analgesic, and shows no significant analgesic effect.
Thus, there reaims a demand for a safe and effective analgesic, particularly a strong analgesic free from addiction and an analgesic to treat pain caused by sensory nerve abnormality such as hyperalgesia, allodynia and the like.
Pain is caused when an algesic substance, which is released upon occurrence of tissue disorder due to nociceptive stimulus (chemical stimulus, mechanical stimulus, thermal stimulus), excites nociceptor (free nerve terminal) at the sensory nerve terminal, and the information of the pain sensation reaches the cerebral cortex and is recognized as pain. In addition, visceralgia is considered to be caused by the contraction of visceral smooth muscle, that mechanically extends and excites the sensory nerve.
Pain sensation is mostly transmitted by two kinds of thin nerve fiber Axcex4 and C fibers, wherein sharp mechanical stimulus conducts myelinated Axcex4 fiber and dull pain conducts unmyelinated C fiber. Typical algesic substance includes bradykinin, serotonin, histamine and the like, that act on nociceptor at the nerve terminal. There is a substance that encourages action of an algesic substance, like prostaglandin synthesized at the inflammation site in the peripheral tissue. Such pain afferent fiber (primary afferent fiber) forms synapse on the surface layer of dorsicornu. The primary afferent fiber excites nociceptive neuron via neurotransmitters, such as excitatory amino acid, substance P and the like, and the information is transmitted from dorsicornu to medulla oblongata, thalamus and to cerebral cortex.
Pressure and tactile sensation is mainly transmitted by thicker Axcex2 fiber which transmits the information from sensory nerve terminal to dorsicornu, medulla oblongata, thalamus and to cerebral cortex, like pain afferent fiber.
Opioid receptors involved in algesia exist in various parts of these spinothalamic tracts. The respiratory suppressive action, nauseant action and the like result from the action on the opioid receptor in the medulla oblongata. While opioid acts on spinal cord, medulla oblongata, thalamus and cerebral cortex to show strong analgesic effect, suppression of thalamus and cerebral cortex is not its main action. Direct suppression of opioid receptor in the dorsicornu neuron and suppression of dorsicornu neuron by descending depression via midbrain and medulla oblongata are considered to be the main action.
Tactile sensation tends to be dull upon sustained application of stimuli of the same intensity. This adaptation is unfeasible in case of pain, but sustained release of neurotransmitter by long-term stimulation of sensory nerve is considered to induce chronic pain by changing the excitatory or information transmission efficiency of the nerve cell. In addition, inhibitory neurotransmitters, such as xcex3-aminobutyric acid (GABA), glycine and the like, suppress excitement of nerves upon activation of each receptor. While allodynia is considered to be partly induced by dull suppression of neurotransmission due to the stimuli repeatedly applied to the sensory nerve, the mechanism of the onset of chronic pain, hyperalgesia and allodynia has been known only to a limited degree.
As described, the sensory nerve transmission is controlled by excitatory nerve fiber and inhibitory nerve fiber in complicated relationship with each other, and many neurotransmitters involved therein have been found to exist. Hence, there are many targets used to find a pharmaceutical agent exhibiting effective analgesic action.
Following the discovery of cerebral morphine receptor in 1973, enkephalin, which is an endogenous pentapeptide having analgesic effect, was first found and isolated in 1975. There are known more than 20 kinds of morphinomimetic peptides under the category of opioid peptide, that inhibit the transmission of algesia information.
These opioids inclusive of morphine act on opioid receptor. The opioid receptor is known to include several subtypes, wherein morphine shows high affinity for xcexc receptor, enkephalin shows high affinity for xcex4 receptor and dynorphin shows high affinity for xcexa receptor, these consisting the base thereof.
It is a long-known fact that involvement of xcexc receptor from among these is important for the analgesic effect and the mechanism thereof has been most elucidated. The study of withdrawal syndrome induction capability and the like of each subtype by the use of opioid antagonist has revealed that the morphine addiction is mainly attributable to the action via xcexc receptor.
An opioid receptor like-1 (ORL-1) receptor has high homology with opioid receptor but does not bind with conventional opioid ligands. This receptor was cloned in 1993.*1*2 In 1995, peptide consisting of 17 amino acids was isolated as endogenous ligand of ORL-1 receptor, and structurally characterized and named Nociceptin or Orphanin FQ *3*4 (*1; FEBS Lett., 341, 33-38, 1994) (*2; FEBS Lett., 347, 284-288, 1994) (*3; Nature, 377, 532-535, 1995) (*4; Science, 270, 792-794, 1995).
The amino acid sequence of nociceptin is similar to that of Dynorphin A which is an endogenous opioid peptide. Dynorphin A is a xcexa receptor agonist showing analgesic effect, but binds weakly with ORL-1 receptor and is said to have no activity*5. Nociceptin binds extremely weakly with an opioid receptor*6, and algesia tests including hot plate test*7 using mouse, scratching of lower abdomen with both hindlimbs of mouse, biting and licking of both hindlimbs (SBL) behavior induction test*8 and the like have revealed its promoting action on transmission of pain information. These reports taught that nociceptin and ORL-1 receptor had specific affinity for each other, and nociceptin was a peptide that induced or amplified pain, conversely from the case of opioid peptide. The study of action mechanism thereof is underway. (*5; Eur. J. Pharmacol., 321, 97, 1997) (*6; J. Biol. Chem., 271, 23642, 1996) (*7; Anesthesia, 45, 1060-1066,1996) (*8; 18th Analgesic.Opioid Peptide Symposium Abstract, 11-14, 1997).
ORL-1 receptor has been reported to express more in the central nerve system, such as cerebral cortex, hypothalamus, spinal cord and the like*9, and nociceptin has been shown to be distributed more on the surface layer of dorsicornu where primary pain afferent fiber terminates*10, and algesia transmission of nociceptin is considered to be mainly through central nerve system (*9; J. Neurochemistry, 64, 34-40, 1995) (*10; Neuro Report 7, 3021-3025, 1996).
It has been also reported that administration of nociceptin induces nociceptive hypersensitivity (hyperalgesia*3*4, allodynia*11) and that it amplifies excitatory stimulus by heat and tactile (*11; Molecular Brain Research, 43, 96-104, 1996).
Under the circumstances, substances reported to exhibit a nociceptin antagonistic action are only nociceptin-like polypeptide and naloxone benzoylhydrazone which is a xcexa receptor antagonist having a morphine-like structure, both of which having ORL-1 receptor affinity, and a pharmaceutical agent having specific antagonistic action on ORL-1 receptor has not been developed.
Known analgesic having a quinoline skeleton includes opioid or anesthetic antagonist analgesic [Japanese Patent Unexamined Publication No. 63-264460 (EP 277794; BOC Inc.)], analgesic having a different action mechanism [Japanese Patent Unexamined Publication No. 62-503030 (U.S. Pat. No. 5,104,884; Alkaloida Vegyeszeti Gyar, antifungal action), WO96/13485 (EP 807105; Fujisawa Pharmaceutical Industries, Ltd., bradykinin antagonist), WO96/11930 (Smithkline beecham P.L.C., serotonin receptor antagonist), Japanese Patent Unexamined Publication No. 59-210084 (U.S. Pat. No. 4,839,366; Chiesi Farmaceutici S.p.A., prostaglandin synthesis inhibition), Japanese Patent Unexamined Publication No. 54-73784 (U.S. Pat. No. 4,293,549; Leo Pharmaceutical Products Limited A/S), FR 1557928 and FR 1543405 (M. Robert ARIES) and the like. These do not include a compound having the structure of the inventive compound, nor do they disclose an action on nociceptin or ORL-1 receptor as in the present invention.
Compounds having a quinoline skeleton structurally similar to that in the inventive compound and which can be used for effects other than analgesic effect are shown in DE 831100 and DE 947552 (anti-blood parasite agent), WO97/14681 (therapeutic agent of bone metabolism abnormality), Japanese Patent Unexamined Publication No. 63-99069 (U.S. Pat. No. 4,753,951; antipsychotic agent), Japanese Patent Unexamined Publication No. 2-167265 (U.S. Pat. No. 5,019,574; psychoneurotic function improving agent), Journal of American Chemistry Society (76, 3703-3708, 1956) (antibacterial agent), HU34479 {disclosure of quinoline skeleton as a synthetic intermediate for imidazo[4,5-c]quinoline derivative (analgesic)} and the like, though none of which discloses effectiveness as an analgesic.
Based on the foregoing findings, a pharmaceutical agent having nociceptin antagonistic action can make an effective agent for pain, particularly sharp pain such as postsurgery pain and the like or pain caused by sensory nerve abnormality, such as hyperalgesia, allodynia and the like, and a safe pharmaceutical agent showing selective action on ORL-1 receptor and free of marked side effects.
It is therefore an object of the present invention to provide a pharmaceutical agent having an action mechanism different from that of known analgesics, via nociceptin antagonistic action.
It is also an object of the present invention to provide a novel compound having a nociceptin antagonistic action, which is useful as an analgesic.
As a result of the intensive study of the present inventors in an attemp to solve the above-mentioned problems, the present invention now provides a novel compound having an analgesic effect.
The present invention specifically provides the following (1) to (20).
(1) A nociceptin antagonist containing an amide derivative of the formula [1]
wherein
R1 and R2 are the same or different and each is hydrogen atom, lower alkyl optionally substituted by hydroxy, amino, lower alkylamino or di(lower)alkylamino;
R3 and R4 are the same or different and each is hydrogen atom, halogen atom or lower alkyl;
ring A is aryl or heterocyclic group;
ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and
X is hydrogen atom, halogen atom, lower alkyl optionally substituted by lower alkoxy, lower alkenyl, amino, cyano or a group of the formula 
wherein
E is a single bond, carbonyl, sulfinyl, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CHxe2x95x90CR6xe2x80x94 wherein R6 is hydrogen atom or aryl or xe2x80x94NR7xe2x80x94 wherein R7 is hydrogen atom, lower alkyl or lower alkoxycarbonyl;
ring G is aryl, heterocyclic group, cycloalkyl or condensed aryl;
R5 is halogen atom, hydroxy, lower alkyl optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy, lower alkoxy optionally substituted by lower alkoxy, amino, lower alkylamino, di(lower)alkylamino, nitro, cyano, lower alkanoyl, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl;
t is 0 or an integer of 1 to 5, which indicates the number of substituents on the ring G, wherein when t is an integer of 2 to 5, each R5 may be the same or different;
m is 0 or an integer of 1 to 8; and
n is 0 or an integer of 1 to 4,
or a pharmaceutically acceptable salt thereof as an active ingredient.
(2) A nociceptin antagonist containing the amide derivative of (1) above wherein the ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient.
(3) A nociceptin antagonist containing the amide derivative of (1) above wherein the ring B is phenyl and X is a group of the formula 
wherein E, ring G, R5, t, m and n are as defined in (1), or a pharmaceutically acceptable salt thereof as an active ingredient.
(4) A nociceptin antagonist containing the amide derivative of (3) above wherein the ring A is 
wherein R8 is lower alkylthio, or a pharmaceutically acceptable salt thereof as an active ingredient.
(5) An amide derivative of the formula [1xe2x80x2]
wherein R2, ring B, E, ring G, R5, t, m and n as defined in (1), or a pharmaceutically acceptable salt thereof.
(6) The amide derivative of (5) above, wherein the ring B is phenyl and R2 is lower alkyl, or a pharmaceutically acceptable salt thereof.
(7) The amide derivative of (6) above, wherein the amino substitutes at the 4-position on a quinoline skeleton, R2 is methyl substituting at the 2-position on the quinoline skeleton, E is xe2x80x94Oxe2x80x94 and the ring B of phenyl has a substituent of the formula 
wherein ring G, R5, t, m and n as defined in (1), at the 2-position, or a pharmaceutically acceptable salt thereof.
(8) The amide derivative of (7) above or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2,4-dichlorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-(phenoxymethyl)benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dimethoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]benzamide,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2,3-dimethoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methylphenoxy)methyl]benzamide,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chlorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxymethoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-cyanophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-trifluoromethylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-nitrophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2-nitrophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2-methoxyphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-aminophenoxy)methyl]benzamide dihydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-chlorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-fluorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dichlorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chlorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-dimethylaminophenoxy)methyl]benzamide dihydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-tert-butylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-(4-biphenylyloxymethyl)benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-isopropylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-bromophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-propylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-fluorophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-trifluoromethylphenoxy)methyl]benzamide hydrochloride,
methyl 4-[2-{N-(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]benzoate hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-iodophenoxy)methyl]benzamide,
N-(4-amino-2-methyl-6-quinolyl)-2-(3-pyridyloxymethyl)benzamide hydrochloride,
4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]benzoate hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(3-cyanophenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-mesylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-ethylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-methylphenoxy)methyl]benzamide hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]benzamide,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide,
4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]benzyl acetate hydrochloride,
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxymethylphenoxy)methyl]benzamide hydrochloride and
N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]benzamide hydrochloride monohydrate.
(9) An amide derivative of the formula [1xe2x80x3]
wherein the ring A, R2, R5 and t are as defined in (1), or a pharmaceutically acceptable salt thereof.
(10) A pharmaceutical composition comprising the amide derivative of any of (5) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
(11) A nociceptin antagonist containing the amide derivative of any of (5) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient.
(12) An analgesic containing the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient.
(13) A method for expressing a nociceptin antagonistic action, comprising administering the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof.
(14) A method for treating pain, comprising administering the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof.
(15) Use of the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof for the production of a nociceptin antagonist.
(16) Use of the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof for the production of an analgesic.
(17) A pharmaceutical composition for antagonizing nociceptin, which comprises the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
(18) A commercial package comprising the pharmaceutical composition of (17) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for antagonizing nociceptin.
(19) A pharmaceutical composition for analgesic use, which comprises the amide derivative of any of (1) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
(20) A commercial package comprising the pharmaceutical composition of (19) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for analgesia.
Each substituent and moiety used in the present specification are defined as follows.
Halogen atom is fluorine atom, chlorine atom, bromine atom or iodine atom. At R3, R4, R5 and R5xe2x80x3, it is preferably chlorine atom.
Lower alkyl has linear or branched chain and 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.
It is preferably a linear or branched alkyl having 1 to 4 carbon atoms. At R3, R4, R7, R9, R10, R11 and R2xe2x80x2, it is more preferably methyl and at R5xe2x80x2, it is more preferably methyl or ethyl.
Lower alkoxy has an alkyl moiety defined above as lower alkyl. Specific examples include methoxy, ethoxy, propoxy, isopropyloxy, tert-butoxy and the like.
Lower alkylthio has an alkyl moiety defined above as lower alkyl. Specific examples include methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R8, it is more preferably methylthio.
Lower alkanoyl has an alkyl moiety defined above as lower alkyl. Specific examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably acetyl.
Lower alkylsulfonyl has an alkyl moiety defined above as lower alkyl. Specific examples include mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably mesyl.
Lower alkanoyloxy has an alkyl moiety defined above as lower alkyl. Specific examples include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably acetoxy.
Lower alkoxycarbonyl has an alkyl moiety defined above as lower alkyl. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably methoxycarbonyl, and at R7, it is more preferably tert-butoxycarbonyl.
Lower alkyl optionally substituted by hydroxy means that the above-defined lower alkyl is optionally substituted by one or more hydroxy, and that the lower alkyl may be unsubstituted. Specific examples include methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1,2-dihydroxyethyl, 2-(hydroxymethyl)butyl and the like.
R1 and R2 are preferably methyl, ethyl, propyl, isopropyl or hydroxymethyl, and more preferably methyl or ethyl.
Lower alkyl optionally substituted by lower alkoxy means the above-defined lower alkyl optionally substituted by the above-defined lower alkoxy, including unsubstituted alkyl. Specific examples include methyl, ethyl, methoxymethyl, ethoxymethyl, 2-(methoxymethyl)butyl and the like.
Preferably, its base alkyl moiety is a linear alkyl having 1 to 4 carbon atoms. At X, it is more preferably methoxymethyl.
Lower alkoxy optionally substituted by lower alkoxy means the above-defined lower alkoxy optionally substituted by the above-defined lower alkoxy, including unsubstituted alkoxy. Specific examples include methoxy, ethoxy, methoxymethoxy, methoxyethoxy, 2-(methoxymethyl)butyloxy and the like.
Preferably, its base alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably methoxy or methoxymethoxy.
Lower alkyl optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy means that the above-defined lower alkyl is optionally substituted by one or more of the above-defined halogen atom, hydroxy, the above-defined lower alkanoyloxy and the above-defined lower alkoxy optionally substituted by lower alkoxy, each of which may be the same or different, and that the lower alkyl may be unsubstituted. Specific examples include methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, acetoxymethyl, pivaloyloxymethyl, bromomethyl, trifluoromethyl, methoxymethoxymethyl, methoxyethoxymethyl and the like.
Preferably, its base alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R5, it is more preferably methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, acetoxymethyl, trifluoromethyl or methoxymethoxymethyl and more preferably ethyl.
Lower alkylamino is a monoalkylamino group wherein the alkyl moiety is defined above as lower alkyl. Specific examples include methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R1 and R2, it is more preferably methylamino.
Di(lower)alkylamino is a dialkylamino group wherein the alkyl moiety is the same or different and as defined above as lower alkyl. Specific examples include dimethylamino, diethylamino, methylethylamino, N-isopropyl N-isobutylamino and the like.
Preferably, its alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms. At R1, R2 and R5, it is more preferably dimethylamino.
Lower alkenyl is linear chain alkenyl having 1 to 6 carbon atoms. Examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2,4-butadienyl, 1-pentenyl, 1,3-pentadienyl and 1,3,5-hexatrienyl and the like.
X is preferably vinyl.
Aryl is an aromatic hydrocarbon group having 6 to 18 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, pyrenyl and the like.
Ring A is preferably phenyl and naphthyl, more preferably phenyl. Ring G and R6 are preferably phenyl.
When ring G is phenyl, substituent R5 is preferably bonded at para-position.
Heterocyclic ring is a cyclic compound group having one or more from oxygen atom, nitrogen atom and sulfur atom as hetero atom, wherein plural hetero atoms may be contained and the number of atoms constituting the ring is 5 to 20. Specific examples thereof include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, benzimidazolyl, imidazolidinyl, indolinyl, pyrrolidinyl, pyrolinyl, piperidinyl, piperazinyl, chromanyl, morpholinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalyl, cinnolinyl, pteridinyl, 4H-quinolizinyl, carbazolyl, 1,3,5-triazinyl, 2,3-dihydrobenzofuranyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroacridinyl, 2,3-dihydro-1H-cyclopenta[b]quinolyl and the like.
Ring G is preferably pyridyl, benzofuranyl or 2,3-dihydrobenzofuranyl, more preferably 2,3-dihydrobenzofuranyl.
Ring A is preferably a cyclic compound group containing one or more nitrogen atoms as hetero atoms, and the number of atoms constituting the ring is 9 to 14. More preferably, it is quinolyl, isoquinolyl, quinoxalyl, benzimidazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroacridinyl or 2,3-dihydro- 1H-cyclopenta[b]quinolyl, most preferably quinolyl, 5,6,7,8-tetrahydroacridinyl or 2,3-dihydro-1H-cyclopenta[b]quinolyl.
When the ring A is quinolyl, it is preferable that R1 be an amino group substituting at the 4-position, R2 be a lower alkyl substituting at the 2-position and xe2x80x94NHCOxe2x80x94 substitute at the 6-position.
Cycloalkyl is a saturated cycloalkyl having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloctyl.
Ring G is preferably cyclohexyl.
Condensed aryl is the above-defined aryl wherein the above-defined cycloalkyl groups are condensed, which is a cyclic compound group wherein the number of atoms constituting the ring is 5 to 18. Specific examples include indanyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro3-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-anthryl, 1,2,3-trihydroazulenyl and the like.
Ring G is preferably 5,6,7,8-tetrahydro-2-naphthyl.
Protected amino is an amino group protected by an amino-protecting group used in a typical chemical synthesis. Specific examples of the amino-protecting group include formyl, acetyl, benzoyl, benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, phthaloyl, benzyl, tosyl and the like.
Carboxy-protecting group is a carboxy-protecting group used in a typical chemical synthesis. Specific examples thereof include methyl, methoxyethoxymethyl, phenacyl, phthalimidomethyl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, tert-butyldimethylsilyl and the like.
Hydroxy-protecting group is a hydroxy-protecting group used in a typical chemical synthesis. Specific examples thereof include trimethylsilyl, tert-butyldimethylsilyl, methyl, benzyl, p-methoxybenzyl, tert-butyl, trityl, tetrahydropyranyl, methoxymethyl, methoxyethoxyethyl, acetyl, benzoyl and the like.
In the above-mentioned formnulas [1], [1xe2x80x2] and [1xe2x80x3], each symbol preferably means the following.
Ring G is preferably aryl.
R5 is preferably halogen atom; lower alkyl optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy; lower alkoxy optionally substituted by lower alkoxy; nitro; cyano; or lower alkanoyl, and more preferably lower alkyl optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy.
The t is preferably 0 or an integer of 1 or 2, more preferably 1.
The E is preferably a single bond or xe2x80x94Oxe2x80x94, more preferably xe2x80x94Oxe2x80x94.
When E is xe2x80x94Oxe2x80x94, m is preferably an integer of 1 to 7, more preferably 1, and n is preferably 0. When E is a single bond, m+n is preferably 2.
The compound of the formula [1] includes various isomers. For example, there exist geometric E- and Z-isomers. When asymmetrical carbon atom(s) exist(s), stereoisomers (e.g., enantiomer and diastereomer) exist. Depending on the case, tautomers may exist in the present invention. Therefore, the present invention encompasses all these isomers and mixtures thereof.
The pharmaceutically acceptable salt thereof may be any salt as long as it can form a nontoxic salt with the compound of the above-mentioned formula [1], [1xe2x80x2] or [1xe2x80x3]. Examples thereof include salts with inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like; salts with organic acid such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid and the like; salts with inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and the like; salts with organic base such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and the like; or salts with amino acid such as lysine, alginine, alanine and the like. The present invention further encompasses water-containing compounds and hydrates and solvates of each compound.
The present invention further encompasses prodrugs and metabolites of each compound. Prodrug is a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group and which shows efficacy upon restoration to its original form after administration to a body, wherein included therein are a complex without a covalent bond and salts.
When the compound of the present invention is used as a pharmaceutical preparation, it is generally admixed with conventionally known pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrator, stabilizer, preservative, buffer, emulsifier, aromatic, coloring agent, sweetener, tackifier, flavor, solubilizer and other additive, specifically water, vegetable oil, alcohol (e.g., ethanol, benzyl alcohol and the like), polyethylene glycol, glycerol triacetate, gelatin, carbohydrate (e.g., lactose, starch and the like), magnesium stearate, talc, lanolin, petrolatum and the like, and formulated into tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like by a conventional method, which can be administered systemically or locally by oral or parenteral administration.
While the dose varies depending on age, body weight, symptom, therapeutic effect, administration route and the like, it is generally 0.01 mg to 1 g per dose which is given once to several times a day for an adult.
One example of the production method of the compound to practice the present invention is explained in the following, to which the production method of the compound of the present invention is not limited.
In each step, the treatment of reaction may be a conventional one, such as isolation and purification, crystallization, recrystallization, silica gel column chromatography, preparative HPLC and the like, which may be appropriately selected and combined. Where necessary, a protecting group may be introduced into a functional group and deprotected for production.
Production Method 1
A synthetic method of the compound of the following formula [I] is shown in the following. 
wherein ring A, R1, R2 and R3 are as defined above.
When ring A is a quinoline ring, the quinoline synthetic method of Camps, the quinoline synthetic method of Combes, the quinoline synthetic method of Friedlander, the quinoline synthetic method of Knorr, the quinoline synthetic method of Niementowski and the like can be used for synthesis. A part of the compound can be obtained as a commercially available reagent.
The Production methods of quinoline ring having substituent are show in the following.
Production Method 1-1
In this production method, xcex2-keto acid ester and aniline compound are reacted to give 4-hydroxyquinoline compound. 
wherein R3 is as defined above, R2xe2x80x2 is lower alkyl and Y is nitro or protected amino.
Step 1
Compound [I-1] and compound [I-2] are condensed in an alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol and the like, at room temperature or under heating to give compound [I-3].
Step 2
Compound [I-3] obtained in Production method 1-1, Step 1 is added by portions to a heated solvent and cyclized to give compound [I-4].
Preferable solvent is diphenyl ether or a mixture of diphenyl ether and diphenyl such as Dowtherm A (trademark Fluka).
This production method can be applied to compound [I-1] wherein the xcex1-position of xcex2-keto acid ester is substituted by lower alkyl.
Production Method 1-2
According to this production method, quinoline compound is obtained from isatin compound. 
wherein R3 and Y are as defined above.
Step 1
Compound [I-5], acetone and aqueous ammonia are reacted under pressurization and under heating to give compound [I-6].
Step 2
Compound [I-6] obtained in Production method 1-2, Step 1 is reacted in the presence of oxidizing agent, such as sodium hypochlorite, sodium hypobromite and the like, under cooling, and the obtained reaction mixture is added dropwise into hot water and further heated to give compound [I-7].
The following production method can be used to introduce a specific substituent or into a specific substitution site.
Production Method 1-3
According to this production method, 4-hydroxy-2-methoxycarbonylquinoline compound is obtained from acetylenedicarboxylate compound and aniline compound. The methoxycarbonyl group of this compound can be converted to hydroxymethyl group by reduction in a later step. 
wherein R3 and Y are as defined above.
Step 1
Compound [I-8] and compound [I-9] are condensed in the same manner as in Production method 1-1, Step 1 to give compound [I-10].
Step 2
Compound [I-10] obtained in Production method 1-3, Step 1 is cyclized in the same manner as in Production method 1-1, Step 2 to give compound [I-11].
Production Method 14
According to this production method, 4,6-diaminoquinoline compound is obtained from 4-nitroquinoline N-oxide compound. 
Step 1
Compound [I-12] and metal iron are reacted in an acid solvent, such as hydrochloric acid, acetic acid and the like, under heating and the resulting solution is made alkaline to give compound [I-13].
Alternatively, a typical reduction using tin or tin (II) chloride and conc. hydrochloric acid; alkaline metal sulfide such as aqueous sodium sulfide solution; catalytic reduction and the like may be used.
Step 2
Compound [I-13] obtained in Production method 1-4, Step 1 is treated with bromine in acetic acid under cooling or at room temperature to halogenate to give compound [I-14].
Alternatively, halogenating agent such as hypohalite (e.g., hypochlorite and the like), N-bromosuccinimide and the like can be used instead of bromine for halogenation.
Step 3
Compound [I-14] obtained in Production method 1-4, Step 2 is subjected to nitration in a sulfuric acid solvent under cooling by adding conc. nitric acid to give compound [I-15].
Nitric acid or inorganic nitrate-sulfuric acid may be used instead of a mixture of nitric acid-sulfuric acid for nitration.
Step 4
Compound [I-15] obtained in Production method 1-4, Step 3 is subjected to catalytic reduction using a hydrogenating catalyst in an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol and the like by adding hydrochloric acid or hydrogen bromide-acetic acid solution at room temperature or under heating under normal pressure to high pressure to give compound [I-16].
Examples of hydrogenating catalyst include palladium carbon, palladium hydroxide, palladium black, Raney-nickel, platinum oxide and the like.
Examples of synthesis when ring A is isoquinoline ring are shown in the following.
Production method 1-5
According to this production method, 1-halogeno-7-nitroisoquinoline is obtained from tetrahydroisoquinoline. 
Step 1
Compound [I-17] is subjected to nitration in the same manner as in Production method 1-4, Step 3 to give compound [I-18].
Step 2
Compound [I-18] obtained in Production method 1-5, Step 1 is subjected to dehydrogenation for a few days using Fremy""s salt in 4% aqueous sodium carbonate solution at room temperature to give compound [I-19].
Step 3
Compound [I-19] obtained in Production method 1-5, Step 2 is reacted with m-chloroperbenzoic acid in a halogen solvent, such as dichloromethane, chloroform, carbon tetrachloride and the like, at room temperature for N-oxidation to give compound [I-20].
Step 4
Compound [I-20] obtained in Production method 1-5, Step 3 is reacted with phosphorus oxychloride in a hydrocarbon solvent, such as toluene, xylene and the like, under heating to give compound [I-21].
Production Method 1-6
According to this production method, quinoline compound condensed with cycloalkyl is obtained by condensation of saturated cyclic ketone and anthranilonitrile compound. 
wherein Y is as defined above and p is 0 or an integer of 1.
An acid catalyst such as Lewis acid (e.g., zinc chloride) is added to a mixture of Compound [I-22] and compound [I-23] under heating for condensation to give compound [I-24].
Production Method 1-7
According to this production method, a substituent of a compound is substituted by amino group or substituted amino group. 
wherein ring A, R2, R3 and Y are as defined above, R9 is hydrogen atom or lower alkyl and R2 is lower alkyl.
Step 1
Compound [I-25] obtained in Production method 1-1 or a commercially available reagent is reacted with chlorosulfonyl isocyanate in acetonitrile or dichloroethane under heating to give compound [I-26].
Step 2
Compound [I-25] obtained in Production method 1-1 or a commercially available reagent is reacted with an alkylating agent in a solvent under heating or at room temperature to give compound [I-27].
As the alkylating agent, dimethyl sulfate or methyl p-toluenesulfonate is used to introduce methoxy group in the scheme.
Examples of preferable solvent include hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; and ether solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like.
Step 3
Compound [I-25] obtained in Production method 1-1 or a commercially available reagent is reacted with halogenating agent, such as phosphorus oxychloride, phosphorus pentachloride and the like, under heating and the reaction mixture is made alkaline to give compound [I-28].
Step 4
Compound [I-28] obtained in Production method 1-5 or Production method 1-7, Step 3 or commercially available reagent is reacted with metal alkoxide in an alcohol solvent, such as methanol, ethanol, propanol, butanol and the like, under heating to give compound [I-27].
As the metal alkoxide, sodium methoxide is used and as the solvent, methanol is used as the corresponding alcohol solvent to introduce methoxy shown in the scheme.
Step 5
Compound [I-27] obtained in Production method 1-7, Step 2 or Production method 1-7, Step 4 or commercially available reagent is reacted with aminating agent such as ammonium acetate and the like under heating to give compound [I-26].
Step 6
Compound [I-28] obtained in Production method 1-7, Step 3 or commercially available reagent is reacted with compound [I-29] in the presence of a base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, under heating to give compound [I-30].
The compound [I-25] in this Production method 1-7 may be compound [I-11] obtained in Production method 1-3.
Production Method 1-8
According to this production method, amino-protecting group of a compound is eliminated or nitro group of a compound is reduced. 
wherein ring A, R1, R2, W and Y are as defined above.
When Y is a protected amino, a typical deprotection method corresponding to the protecting group is used.
For example, when the protecting group is acetyl, conc. hydrochloric acid is added to compound [I-31] obtained in Production method 1-7 or a commercially available reagent, and the mixture is heated for deacetylation to give compound [I].
Instead of conc. hydrochloric acid treatment, heating in conc. ammonia, potassium hydroxide treatment and the like may be used.
When Y is nitro, a typical method of conversion to amine by reduction of nitro is used. For example, compound [I-31] obtained in Production method 1-7 or commercially available reagent is subjected to catalytic reduction in a solvent at room temperature or under heating, at normal pressure or high pressure using a hydrogenating catalyst to give compound [I].
Examples of the solvent include ether solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like; alcohol solvent such as methanol, ethanol, propanol, butanol and the like; ester such as ethyl formate, ethyl acetate, butyl acetate and the like; water; or a mixed solvent thereof.
The hydrogenating catalyst is exemplified by palladium carbon, palladium hydroxide, palladium black, Raney-nickel, platinum oxide and the like.
Production Method 2
The synthetic method of the compound of the formula [II] is shown in the following. 
wherein ring B, R4 and X are as defined above.
When X is a group of the formula 
wherein ring G, R5 and t are as defined above, the following Production method is exemplified.
Production Method 2-1
According to this production method, methyl of a methyl-substituted carboxylic acid compound is converted to ether. 
wherein ring B, ring G, R4, R5 and t are as defined above, and Z is a carboxy-protecting group.
Step 1
Compound [II-1] is reacted with radical initiator such as benzoyl peroxide, azobisisobutyronitrile and the like and N-bromosuccinimide to give compound [II-2].
Step 2
Compound [II-2] obtained in Production method 2-1, Step 1 is reacted with compound [II-3] in a solvent in the presence of a base, such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like, under heating to give compound [II-4].
Examples of the solvent include hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; ether solvent such as 1,4-dioxane, diethylether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like; and alcohol solvent such as methanol, ethanol, propanol, butanol and the like.
Most of compound [II-3] can be easily obtained as a commercially available reagent but a compound difficult to obtain can be synthesized by the following production methods.
Production Method 2-2
According to this production method, a cyclic compound having a substituent is substituted by halogen atom. 
wherein ring G is as defined above, R5xe2x80x2 is lower alkyl and R5xe2x80x3 is halogen atom.
In the same manner as in Production method 1-4, Step 2, compound [II-5] is halogenated to give compound [II-6].
Using sulfuryl chloride as the halogenating agent, the compound is halogenated in a halogen solvent, such as dichloromethane, chloroform, carbon tetrachloride, tetrachloroethylene and the like, to substitute chlorine atom at the ortho-position of 4-alkyl substituted phenol.
Production Method 23
According to this production method, a cyclic compound is substituted by alkylsulfonyl. 
wherein ring G is as defined above, Q is a hydroxy-protecting group and R11 is lower alkyl.
Step 1
Compound [II-7] is reacted with alkylsulfonic anhydride, such as methanesulfonic anhydride, in a halogen solvent, such as dichloromethane, chloroform, carbon tetrachloride, tetrachloroethylene and the like, under heating to give compound [II-8].
Step 2
Compound [II-8] obtained in Production method 2-3, Step 1 is deprotected by a conventional method to give compound [II-9].
For example, when R11 is methyl, aqueous hydrogen bromide is added and heated, or heated with sodium cyanide in dimethyl sulfoxide to allow deprotection.
Production Method 2-4
According to this production method, benzofuran compound or 2,3-dihydrobenzofuran compound is synthesized from phenol compound. 
wherein Q is as defined above.
Step 1
Compound [II-10] is condensed with compound [II-11] in a polar solvent, such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like, in the presence of a base, such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like, under heating to give compound [II-12].
Step 2
Compound [II-12] obtained in Production method 2-4, Step 1 is cyclized using an agent for condensation, such as polyphosphoric acid and the like, in a hydrocarbon solvent, such as benzene, toluene, hexane, xylene and the like, under heating to give compound II-13].
Step 3
Compound [II-13] obtained in Production method 2-4, Step 2 is subjected to catalytic reduction in the same manner as in Production method 1-4, Step 4 to give compounds [II-14] and [II-15].
Examples of the solvent include, besides alcohol solvents, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like and a mixed solvent thereof and the like.
Production Method 2-5
According to this production method, a carboxy-protecting group is eliminiated from a compound. 
wherein ring B, R4, X and Z are as defined above.
The carboxy-protecting group can be eliminated by a conventional deprotection method depending on the kind of protecting group.
For example, when Z is methyl, compound [II-16] is reacted in an alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol and the like, in the presence of a base, such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, under heating for deprotection, and the resulting solution is acidified to give compound [II].
Production Method 3
According to this production method, amine compound and carboxylic acid compound are condensed to amine. 
wherein ring A, ring B, R1, R2, R3, R4 and X are as defined above.
Compound [I] obtained in Production method 1 or a commercially available reagent and compound [II] obtained in Production method 2 or a commercially available reagent are condensed by a conventional method of formation of amide by condensation.
For example, compound [II] is treated with a halogenating agent, such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in a solvent at room temperature to give the corresponding acid chloride. Then, the compound is condensed with compound [I] in the presence of a tertiary amine, such as triethylamine and the like, or pyridine at room temperature or under cooling to give compound [1].
Examples of preferable solvent include halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like.
Alternatively, compound [I] and compound [II] are reacted in a solvent in the presence of an agent for condensation at room temperature to give compound [1]. For smooth reaction, an enhancer may be used.
Examples of the agent for condensation include N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-disopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the like and examples of the enhancer include hydroxysuccinimide, 1-hydroxybenzotriazole and the like.
Examples of preferable solvent include a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; a halogen solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; an ether solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; a polar solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; and a mixed solvent thereof.
For an improvement of the yield, reduction of cost and the like to lead to higher production efficiency, reduction, deprotection and the like may be carried out after formation of amide by condensation.
For example, when compound [I] or compound [II] has a nitro group, the nitro group may be reduced after formation of amide by condensation, or when compound [II] and compound [II] have a functional group such as hydroxy and the like, deprotection may be carried out after formation of amide by condensation.
Alternatively, methoxycarbonyl-substituted compound obtained in Production method 1-3 and Production method 3 is added to an ether solvent, such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like, and lithium tetrahydroborate is added by portions in an argon stream under cooling for reduction to give hydroxymethyl-substituted compound.